Synthesis, α-amylase inhibitory activity evaluation and in silico molecular docking study of some new phosphoramidates containing heterocyclic ring

Article abstract of DOI:10.1080/10426507.2020.1845679

We have synthesized a series of phosphoramidates containing a heterocyclic moiety with good yields (88–95%) by the reaction of (E)-5-benzylidene-3-((2-hydroxyethoxy)methyl)thiazolidine-2,4-dione with ethyl phosphorodichloridate followed by the reaction with various heterocyclic amines. The designed compounds were primarily screened for their ability to inhibit pancreatic α-amylase enzyme using in silico molecular docking approach. The compounds with good binding energies (?8.0 to ?6.9 kcal/mol) when compared with standard drug, acarbose (?8.0 kcal/mol) were prompted for the synthesis. The structures of the newly prepared compounds were confirmed by their spectroscopic analyses. They were further screened in?vitro for their inhibition toward α-amylase enzyme using acarbose as standard drug. All compounds exhibited moderate to good inhibition potential with IC₅₀ values in the range of 54.14 ± 0.35 to 185.04 ± 0.53 μg/mL when compared with the standard drug (IC₅₀, 50.47 ± 0.28 μg/mL). Especially, the compound (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl ethyl 1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylphosphoramidate (6f) (IC₅₀, 54.14 ± 0.35 μg/mL) and (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl ethyl benzo[d]thiazol-2-ylphosphoramidate (6c) (IC₅₀, 57.02 ± 0.32 μg/mL) exhibited the best inhibition among the synthesized compounds.

Full text of DOI:10.1080/10426507.2020.1845679

Phosphorus, Sulfur, and Silicon and the Related Elements
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Synthesis, α-amylase inhibitory activity evaluation
and in silico molecular docking study of some new
phosphoramidates containing heterocyclic ring
SK. Md. Altaff , T. Raja Rajeswari & Ch. Subramanyam
To cite this article: SK. Md. Altaff , T. Raja Rajeswari & Ch. Subramanyam (2020): Synthesis,
α-amylase inhibitory activity evaluation and inꢀsilico molecular docking study of some new
phosphoramidates containing heterocyclic ring, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2020.1845679
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1845679
Synthesis, a-amylase inhibitory activity evaluation and in silico molecular
docking study of some new phosphoramidates containing heterocyclic ring
a
b
c
SK. Md. Altaff , T. Raja Rajeswari , and Ch. Subramanyam
a
c
b
Department of Chemistry, Govt. Junior College, Bellamkonda, India; Department of Chemistry, Govt. Degree College, Eluru, India;
Department of Chemistry, Bapatla Engineering College, Bapatla, India
ABSTRACT
ARTICLE HISTORY
We have synthesized a series of phosphoramidates containing a heterocyclic moiety with good
yields (88–95%) by the reaction of (E)-5-benzylidene-3-((2-hydroxyethoxy)methyl)thiazolidine-2,4-
dione with ethyl phosphorodichloridate followed by the reaction with various heterocyclic amines.
The designed compounds were primarily screened for their ability to inhibit pancreatic a-amylase
enzyme using in silico molecular docking approach. The compounds with good binding energies
Received 13 July 2020
Accepted 30 October 2020
KEYWORDS
Phosphoramidates; thiazoli-
dine-2,4-dione; a-amylase;
acarbose; molecular
docking approach
(
ꢀ8.0 to ꢀ6.9 kcal/mol) when compared with standard drug, acarbose (ꢀ8.0 kcal/mol) were
prompted for the synthesis. The structures of the newly prepared compounds were confirmed by
their spectroscopic analyses. They were further screened in vitro for their inhibition toward a-amyl-
ase enzyme using acarbose as standard drug. All compounds exhibited moderate to good inhib-
ition potential with IC50 values in the range of 54.14 ± 0.35 to 185.04 ± 0.53 mg/mL when compared
with the standard drug (IC50, 50.47 ± 0.28 mg/mL). Especially, the compound (E)-2-((5-benzylidene-
2
,4-dioxothiazolidin-3-yl)methoxy)ethyl ethyl 1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
ylphosphoramidate (6f) (IC , 54.14 ± 0.35 mg/mL) and (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-
50
yl)methoxy)ethyl ethyl benzo[d]thiazol-2-ylphosphoramidate (6c) (IC50, 57.02 ± 0.32 mg/mL) exhib-
ited the best inhibition among the synthesized compounds.
GRAPHICAL ABSTRACT
Introduction
applications of PRs in diverse fields of chemistry, mostly in
pharmacy, tremendous interest has been paid to synthesize
this class of compounds.
The compounds containing heterocyclic ring systems are
of great importance due to their established efficacy in
Organophosphorus (OP) chemistry has been growing rapidly
since organophosphorus compounds occupy a variety of bio-
logical processes. In medicine and agriculture these mole-
[
1]
cules play a vital role. Especially, phosphoramidates (PRs),
which are a leading group of OP compounds, exhibit abroad medicinal chemistry. Compounds bearing heterocyclic sys-
[
16]
range of biological activities and are useful as prodrug moi- tems such as thiazole, benzothiazole,
thiazolidine-2,4-
[
17]
[18]
[19]
eties to enhance the therapeutic potential of the parent dione,
pyrazole,
pyrrole, indole,
1,3,4-oxadiazoles, 1,2,3-triazole,
have been proven to be good anti-diabetic agents in the
treatment of T2DM. Thiazolidinediones (TZDs) are oral
benzoxazolone,
[
2,3]
[
20]
[21]
[22]
drug.
In recent years, drugs possessing phosphoramidate
oxazolone,
furan
[
4]
[5]
[7]
moiety have played a vital role to treat diabetes, cancer,
Alzheimer’s disease, and are used in antitumor therapy.
PRs are also useful as cardioprotective, antibacterial, anti-
[
6]
[
8]
[
9]
[10]
[11]
[12] anti-diabetic drugs that control type 2 diabetes via enhance-
oxidants, antiviral,
Figure 1). On the other hand, OP compounds containing
heterocyclic systems have received considerable attention
due to their variety of attractive pharmacological proper- the TZD category. They act as PPARc agonists and showing
anti-HIV
and antigene agents
ment of insulin sensitivity. Pioglitazone, Rosiglitazone and
(
Lobeglitazone (Figure 2) are examples of drugs belonging to
[
13–15]
ties.
Due to the immense efficacy and possible their effectiveness in controlling T2DM. They are effective
CONTACT Tiruveedula Raja Rajeswari
rajarajeswarit865@gmail.com
Government Degree College, Eluru 534001, Andhra Pradesh, India.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1845679.
ß 2020 Taylor & Francis Group, LLC

2
SK. MD. ALTAFF ET AL.
Figure 1. Some biologically active phosphoramidares.
in controlling T2DM however hepatotoxicity is certainly one Results and discussion
[
23]
of their severe side effects.
Chemistry
On the other hand, decreasing the post-prandial glucose
levels by delaying the absorption of glucose via inhibition of We undertook an efficient protocol for the preparation of new
the carbohydrate-hydrolysing enzyme, a-amylase is one of PRs containing heterocyclic moiety (6a–j) with good yields
[
24]
the best approach to fight against T2DM.
In animals, (88–95%) using 2,4-thiazolidinedione as a starting material.
inhibitors of a-amylase reduce the glucose levels (that can The schematic representation for the preparation of these tar-
arise after a meal) by slowing down the speed with which get molecules 6a–j is shown in Scheme 1.
a-amylase can convert starch to simple sugars until the body
The structures of all the prepared compounds were confirmed
[
25]
31
1
13
can deal with it.
Several a-amylase inhibitors, like acar- by NMR ( P, H, C), IR spectroscopy, mass, and elemental
31
bose, miglitol, and voglibose (Figure 2) are currently in use analyses. The P NMR signals of the synthesized compounds
[
26–28]
[34]
as medicine for T2DM.
Nevertheless, these drugs have (6a–j) are observed as singlet in the range 22.1.5–15.5 ppm.
1
several side effects like hepatotoxicity, diarrhea, flatulence, The H NMR spectra gave a multiplet due to aromatic protons in
[
29–32]
and abdominal distension.
looking forward for novel drug candidate to treat T2DM 8.16–8.15 as a singlet were assigned to methine protons, 5.75–3.64
with a better safety profile.
as a multiplet for methylene protons and at 1.23 ppm as a triplet
Hence, researchers are the range of d 7.53–7.25 ppm. The proton signals in the range of
13
Our recent studies demonstrated that, OP compounds for methyl protons of compounds 6a–j. C NMR chemical shifts
containing TZD moiety exhibit significant inhibition for methine, methylene and methyl carbon were observed at d
[
33]
toward the a-amylase enzyme.
With this motivation, 142.7, 71.2–65.3 and 16.4 ppm, respectively. The chemical shifts
in the present study we have designed some novel PRs for the carbonyl carbon were observed at d 171.2 for all the title
and incorporated some heterocyclic amines at the phos- compounds. In order to confirm the functional groups present in
phorus atom. These designed structures were applied to the title compounds, an infrared spectral study has been made.
molecular docking studies. Based on the results obtained The IR spectra of the title compounds displayed strong absorption
ꢀ
1
from these studies, structures which exhibited good bind- bands at 3329–3275 and 1724–1682 cm for secondary amine
ing affinity for the target protein were selected for the and carbonyl groups, respectively. The stretching vibrations for
synthesis and screened for their in vitro a-amylase inhib- P¼ O and P–O–C
were observed at 1237–1221 and
ition assay. The majority of the synthesized compounds 1019–1011 cm , respectively, for compounds 6a–j. All the title
alip
ꢀ
1
þ.
exhibited good activity when compared with the stand- compounds gave M ions as base peaks and isotopic cluster peaks
ard drug.
with expected ratio. The calculated values of elemental analyses

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Figure 2. Some known anti-diabetic drugs.
Scheme 1. Synthesis of phosphoramidates 6a–j.
for the synthesized compounds were in good agreement with the active. From the docking results, it was observed that com-
observed values. The representative spectra of compounds 6a–j pounds 6f, 6c, 6g, 6a and 6j exhibited good binding energies
are available in the Supplemental Materials (Figures S1–S30).
(ꢀ8.0, ꢀ7.9, ꢀ7.9, ꢀ7.8 and ꢀ7.5 kcal/mol) with the target
enzyme, a-amylase when compared with the reference drug
(
ꢀ8.0 kcal/mol) and were fitted in the active site of the target
Pharmacology
gene properly. Binding energies and bonding pose of ligands
with target enzyme are presented in detail in Table S1 (see
In silico molecular docking studies
The docking studies were performed for the newly designed Supplemental Materials). To understand the interactions
molecules 6a–j to understand the binding interactions of the between ligands and the target protein, 2D diagrams are widely
PR derivatives with the active site of the pancreatic a-amylase used in the scientific literature. 2D ligand interactions of most
enzyme (PDB ID: 3IJ8) using 1-click docking online server active compounds (6c, 6d, 6f and 6j) with the target enzyme
tool. 1-Click docking is a web-based server (http://mcule.com/ are shown in Table 1.
apps/1-click-docking/) powered by AutoDock Vina docking
algorithm.
Compound 6f is the most active compound in this series
Ten compounds in this series were found to be and the binding mode shows that the carbonyl oxygen of 1,3-
[35]

4
SK. MD. ALTAFF ET AL.
Table 1. 2D lig plot images of compounds 6c, 6d, 6j and 6f.
Compd. 2D structure
Compd.
2D structure
6
c
6f
6
d
6j
dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
forms a hydrogen bond with the Lys200. Additionally, the pyr- Nickavar and Amin,
imidine and the phenyl ring forms p–p stacking with Lys200 et al with slight modifications.
moiety 200 mg/mL concentrations using the method according to
[
36]
which was at first proposed by Patil
[
37]
The analysis results
and Tyr62, respectively. Additionally, the compound was also (Figure 3) of 6a–j showed that all the derivatives exhibit
found to have hydrophobic interactions with Tyr 62, Trp59, good a-amylase inhibition activity with IC50 values in the
Trp58, Leu165, Leu162, Tyr151, Ala198, Ile235 and Val234. In range of 54.61 ± 0.08 to 185.59 ± 0.74 when compared with
compound 6c, the benzothiazole and phenyl ring forms p–p the standard drug, acarbose whose IC50 was found to be
stacking with His201 and Trp99, respectively. Additionally, 50.78 ± 0.54 (Figure 4). Especially compound 6f, bearing 1,3-
Val234, Ile235, Ala198, Tyr151, Ala307, Trp99, Tyr62, Leu165 dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
moiety
and Leu162 form hydrophobic contacts with compound 6c. In (IC50, 54.14±0.35mg/mL); 6c bearing with benzo[d]thiazol-2-yl
compound 6d, hydrogen bonds are observed between the oxy- motif (IC50, 57.02 ±0.32 mg/mL); 6d incorporated with 6-nitro-
gen atoms of nitro group and Ile235 as well as Lys200. The benzo[d]thiazol-2-yl motif (IC50, 63.91 ±0.33 mg/mL) and 6j
benzothiazole and phenyl groups of this compound formed bearing with 4,5-dimethylisoxazol-3-yl moiety (IC50
,
p–p stacking with His201 and Tyr62, respectively. A salt bridge 65.65 ±0.22 mg/mL) exhibited good inhibition when compared
was also observed between nitrogen atom of nitro group and with the standard drug, acarbose (IC50, 50.47±0.28mg/mL).
Glu233 as well as oxygen atom of nitro group and Lys200. In The left over compounds 6h, 6a, 6e, 6g, 6b and 6i showed
addition to this, compound 6d formed hydrophobic interaction moderate inhibition on the enzyme with IC50 values in the
with Val234, Ile235, Ala198, Tyr151, Leu162, Leu165, Trp58, range 98.30 ±0.62 to 185.04 ±0.53 mg/mL.
Trp59 and Tyr62. The binding mode orientation of compound
6
j shows the formation of p–p stacking between the dimethyli-
Experimental
soxazole group and phenyl ring with His201 and Tyr62,
respectively. Besides, compound 6j forms hydrophobic inter- Materials and characterization techniques
action with Leu165, Leu162, Tyr151, Tyr62, Trp59, Trp58,
Ala198, Ala307, Ile235 and Val234.
The chemicals were purchased from Sd. Fine Chem. Ltd.,
India and a few of them were purified using standard proce-
dures. The purity of the compounds was checked by TLC on
Al sheet of silica gel. The reaction to synthesize the title com-
a-Amylase inhibitory activity
All the newly synthesized compounds were scrutinized for pounds was carried out on magnetic agitator cum hot plate. J
their a-amylase inhibitory activity at 25, 50, 100, 150 and (coupling constants) and d (chemical shift) values were

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
benzylidenethiazolidine-2,4-dione (2). Completion of the reac-
tion was confirmed using TLC using benzene:ethyl acetate as
ꢁ
eluent (3:7). Bright yellow solid; m.p. 218–220 C; Yield: 94%;
1
H NMR (400 MHz, d, ppm, DMSO-d ): 12.10 (s, 1H, NH),
6
13
7
.72 (s, 1H, –CH¼), 7.65–7.42 (m, 5H, Ar–H). C NMR
(
400 MHz, d, ppm, DMSO-d ): 168.4 (C-3), 166.2 (C-1), 142.4
6
(C-6), 134.8 (C-7), 127.6 (C-9, C-11), 127.3 (C-8, C-12), 127.2
(C-10), 117.0 (C-5).
Synthesis of (E)-5-benzylidene-3-((2-hydroxyethoxy)methyl)
thiazolidine-2,4-dione (4)
(E)-5-benzylidenethiazolidine-2,4-dione (2) (2.5g, 10mmol) in
THF was treated with sodium hydride (0.24 g, 10 mmol) at
ꢁ
0
–5 C for 1 h to give sodium salt of compound 2. To this salt,
diiodomethane (0.81 mL, 10 mmol) in tetrahydrofuran (THF)
Figure 3. a-Amylase inhibition activity results of phosphoramidate deriva-
tives (6a–j).
ꢁ
(30 mL) was added slowly at 5 C and stirring was continued
for about 3 h at room temperature. Then the reaction mixture
was filtered to remove sodium iodide. The filtrate contained
(
E)-5-benzylidene-3-(iodomethyl)thiazolidine-2,4-dione.
compound was then treated with ethane-1,2-diol (0.6 mL,
0 mmol) in the presence of triethylamine (0.73 mL, 10 mmol)
This
1
as base for 4 h to give crude product. The progress of the reac-
tion was monitored by TLC using ethyl acetate-hexane (6:4) as
an eluent. The pure compound (E)-5-benzylidene-3-((2-
hydroxyethoxy)methyl)thiazolidine-2,4-dione (3) was obtained
ꢁ
by recrystallization from methanol. Solid, m.p. 231–233 C,
1
Yield: 95%, H NMR (400 MHz, d, ppm, DMSO-d ): 7.74 (s,
6
1
H, ¼CH), 7.63–7.35 (m, 5H, Ar–H), 5.43 (s, 1H, –N–CH ),
2
4
.74 (s, 1H, –OH), 3.39 (t, J¼ 7.6 Hz, 2H, –CH ), 3.27 (t,
2
13
J¼ 6.4 Hz, 2H, –CH ). C NMR (400MHz, d, ppm, DMSO-
2
d ): 171.8 (C-3), 164.0 (C-1), 142.5 (C-6), 134.9 (C-7), 127.4
6
(C-9, C-11), 127.1 (C-8, C-12), 127.0 (C-10), 117.3 (C-5), 71.6
Figure 4. IC50 values of phosphoramidates 6a–j.
(C-13), 63.4 (C-15), 64.7 (C-16).
reported in Hz and ppm, respectively. Bruker AMX spectrom-
[
39]
31
1
Synthesis of PRs 6a–j
eter was used to record P (161.9 MHz), H (400 MHz) and
13
To compound 3 (2.79 g, 10 mmol) in THF (25 mL) was
added a solution of ethyl phosphorodichloridate (1.2 mL,
0 mmol) in THF (25 mL) drop wise in the presence of tetra
methyl guanidine (TMG) (10 mmol) with stirring for about
C (100 MHz) NMR spectra. The symbol ‘s’ for singlet, ‘d’ for
doublet, ‘t’ for triplet and ‘m’ for multiplet were used to repre-
sent peaks in NMR spectra. LC–MS were recorded on
SHIMADZU 2010A. T. F. Flash 1112 apparatus was used for
CHN analysis. Bruker IFS 55 (Equinox) FTIR spectrometer in
KBr was used to record IR spectra. Marvin view software was
utilized to draw the structures, to optimize and convert them
into required format. 1-Click docking software powered by
Auto Dock Vina docking algorithm was used for docking stud-
ies. Graph Pad Prism 8.4.3 (686) software was used to calculate
IC50 values and to draw the corresponding graphs.
1
1
5 min. After the addition was completed, stirring was con-
ꢁ
tinued for about 3 h at 5–10 C. Once the reaction was com-
pleted, as checked by TLC using hexane:ethyl acetate (3:7)
as eluent, the reaction mixture was filtered to remove tetra
methyl guanine hydrochloride to yield (E)-5-benzylidene-3-
(2-hydroxyethoxy)methyl)thiazolidine-2,4-dione (4). To this
compound, pyridin-3-amine (5a) (0.094 g, 10 mmol) in THF
(
(
0
30 mL) was added in the presence of TMG (10 mmol) at
C with stirring and the stirring was continued for 4 h at
ꢁ
Procedures
reflux temperature. Once the reaction was completed as
checked by TLC using hexane:ethyl acetate (4:6) as eluent;
the reaction mixture was filtered to remove tetra methyl
[
38]
Synthesis of 5-benzylidene-2,4-thiazolidinediones (2)
A mixture of 2,4-thiazolidinedione, (1) (2.4 g, 20 mmol), ben-
zaldehyde, (2.12 g, 20 mmol), piperidine (1.4 g, 16 mmol) and guanine hydrochloride. The solvent from the filtrate was
ethanol (150 mL) in a round bottomed flask was refluxed for removed using rota evaporator to acquire crude product. It
2
0 h. The reaction mixture was poured into water (250 mL) was washed twice with chloroform and recrystallized from
and acidified with acetic acid to give compound 3 as solid, ethanol to obtain (E)-2-((5-benzylidene-2,4-dioxothiazolidin-
which was recrystalized from methanol to form pure (E)-5- 3-yl)methoxy)ethyl ethyl pyridin-3-ylphosphoramidate (6a).

6
SK. MD. ALTAFF ET AL.
ꢀ
1
The similar experimental protocol was applied to synthesize 17.6 ppm; IR (KBr) (ꢀmax cm ): 3296 (NH), 1716, 1691
the remaining compounds 6b–j.
(C ¼ O), 1228 (P ¼ O), 1015 (P–O–Calip); LC–MS (m/z, %):
þ
5
20 (M þ H , 100); For C H N O PS ; calcd: C, 50.86; H,
22
22
3
6
2
4
.27; N, 8.09%; found: C, 50.93; H, 4.19; N, 8.16%.
Characterization of title compounds 6a–j
(
E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
(
E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
ethyl pyridin-3-ylphosphoramidate (6a). Yield: 92%; solid,
ethyl 6-nitrobenzo[d]thiazol-2-ylphosphoramidate (6d). Yield:
9
8
ꢁ
1
m.p. 243–244 C; H NMR (DMSO-d ): 8.25 (d, J ¼ 8.4 Hz,
6
ꢁ
1
4%; solid, m.p. 266–268 C;
H
NMR (DMSO-d6):
1
H, Pyridine–H), 8.16 (s, 1H, ¼C–H), 8.09 (s, 1H,
.55–7.25 (m, 8H, Ar–H), 8.16 (s, 1H, ¼C–H), 6.35 (s, 1H,
Pyridine–H), 7.53 (d, J ¼ 7.2 Hz, 2H, Ar–H), 7.36 (t,
J ¼ 7.2 Hz, 2H, Ar–H), 7.30 (t, J ¼ 7.2 Hz, 1H, Pyridine–H),
N–H), 5.75 (s, 2H, –CH –), 4.36 (m, 2H, O–CH CH ), 4.18
2
2
3
(
(
(
q, 2H, P–O–CH –), 3.64 (t, J ¼ 6.0 Hz, 2H, O–CH –), 1.23
2
2
7
.25 (t, J ¼ 6.4 Hz, 1H, Ar–H), 7.20 (d, J ¼ 6.8 Hz, 1H,
13
t, J ¼ 6.8 Hz, 3H, O–CH CH ); C NMR (DMSO-d ): 171.2
2
3
6
Pyridine–H), 6.35 (s, 1H, N–H), 5.75 (s, 2H, –CH –), 4.36
2
C-3), 163.2 (C-1), 157.9 (C-25), 145.1 (C-28), 142.7 (C-6),
34.6 (C-7), 130.3 (C-30), 127.7 (C-9, C-11), 127.3 (C-8, C-
12), 126.8 (C-10), 122.5 (C-27), 118.7 (C-29), 117.5 (C-5),
(m, 2H, O–CH CH ), 4.18 (q, 2H, P–O–CH –), 3.64 (t,
2 3 2
1
J ¼ 6.0 Hz, 2H, O–CH –), 1.23 (t, J ¼ 6.8 Hz, 3H,
2
1
3
O–CH CH ); C NMR (DMSO-d ): 171.2 (C-3), 163.2 (C-
2
3
6
1
1
1
16.8 (C-26), 73.6 (C-23), 71.2 (C-13), 65.6 (C-15), 65.3 (C-
1
1
1
6
), 144.4 (C-23), 142.7 (C-6), 136.7 (C-26), 135.5 (C-24),
34.6 (C-7), 127.7 (C-9, C-11), 127.3 (C-8, C-12), 126.8 (C-
0), 124.4 (C-27), 122.3 (C-28), 117.5 (C-5), 71.2 (C-13),
3
1
6), 61.7 (C-20), 16.4 (C-21);
P NMR (DMSO-d6):
ꢀ
1
8.5 ppm; IR (KBr) (ꢀmax cm ): 3312 (NH), 1719, 1695
31
(C ¼ O), 1233 (P ¼ O), 1018 (P–O–Calip); LC–MS (m/z, %):
5.6 (C-15), 65.3 (C-16), 61.7 (C-20), 16.4 (C-21); P NMR
þ
ꢀ
1
565 (M þ H , 100); For C H N O PS ; calcd: C, 46.81; H,
22
21
4
8
2
(DMSO-d ): 15.5 ppm; IR (KBr) (ꢀmax cm ): 3118 (NH),
6
3
.75; N, 9.92%; found: C, 46.88; H, 3.68; N, 9.98%.
1
730, 1681 (C ¼ O), 1212 (P ¼ O), 1012 (P–O–Calip); LC–MS
þ
(
5
m/z, %): 464 (M þ H , 100); For C H N O PS; calcd: C,
20
22 3 6
(
E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
1.83; H, 4.78; N, 9.07%; found: C, 51.91; H, 4.70; N, 9.14%.
ethyl 6-methoxybenzo[d]thiazol-2-ylphosphoramidate (6e).
Yield: 89%; solid, m.p. 281–282 C; H NMR (DMSO-d ):
8
ꢁ
1
6
(E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
.15 (s, 1H, ¼C–H), 7.53–7.25 (m, 8H, Ar–H), 6.35 (s, 1H,
ethyl thiazol-2-ylphosphoramidate (6b). Yield: 90%; solid,
ꢁ
1
N–H), 5.75 (s, 2H, –CH –), 4.36 (m, 2H, O–CH CH ), 4.18
2
2
3
m.p. 255–257 C; H NMR (DMSO-d ): 8.16 (s, 1H, ¼C–H),
6
(
2
q, 2H, P–O–CH –), 3.81 (s, 3H, OCH ), 3.64 (t, J ¼ 6.0 Hz,
2
3
7
.53 (d, J ¼ 7.2 Hz, 2H, Ar–H), 7.36 (t, J ¼ 7.2 Hz, 2H,
1
3
H, O–CH –), 1.23 (t, J ¼ 6.8 Hz, 3H, O–CH CH );
C
2
2
3
Ar–H), 7.30 (d, J ¼ 8.4 Hz, 1H, Thiazole–H), 7.25 (t,
J ¼ 6.4 Hz, 1H, Ar–H), 6.84 (d, J ¼ 8.0 Hz, 1H, Thiazole–H),
NMR (DMSO-d ): 171.2 (C-3), 163.2 (C-1), 154.7 (C-28),
6
1
(
1
(
43.9 (C-25), 142.7 (C-6), 134.6 (C-7), 131.4 (C-30), 127.7
C-9, C-11), 127.3 (C-8, C-12), 126.8 (C-10), 117.8 (C-26),
17.5 (C-5), 116.7 (C-27), 104.9 (C-29), 73.5 (C-23), 71.2
C-13), 65.6 (C-15), 65.3 (C-16), 61.7 (C-20), 54.9 (C-33),
6
.35 (s, 1H, N–H), 5.75 (s, 2H, –CH –), 4.36 (m, 2H,
2
O–CH CH ), 4.18 (q, 2H, P–O–CH –), 3.64 (t, J ¼ 6.0 Hz,
2
3
2
13
2
H, O–CH –), 1.23 (t, J ¼ 6.8 Hz, 3H, O–CH CH );
C
2
2
3
NMR (DMSO-d ): 171.2 (C-3), 163.2 (C-1), 142.7 (C-6),
6
31
1
6.4 (C-21); P NMR (DMSO-d ): 17.9 ppm; IR (KBr)
6
1
1
7
2
3
37.4 (C-25), 134.6 (C-7), 127.7 (C-9, C-11), 127.3 (C-8, C-
2), 126.8 (C-10), 117.5 (C-5), 115.2 (C-26), 73.4 (C-23),
1.2 (C-13), 65.6 (C-15), 65.3 (C-16), 61.7 (C-20), 16.4 (C-
ꢀ
1
(
1
ꢀmax cm ): 3286 (NH), 1712, 1688 (C ¼ O), 1226 (P ¼ O),
þ
014 (P–O–C ); LC–MS (m/z, %): 550 (M þ H , 100); For
alip
3
1
ꢀ1
C H N O PS ; Calcd: C, 50.27; H, 4.40; N, 7.65%; found:
C, 50.34; H, 4.31; N, 7.74%.
1); P NMR (DMSO-d ): 18.2 ppm; IR (KBr) (ꢀ
cm ):
max
23 24
3
7
2
6
287 (NH), 1714, 1682 (C ¼ O), 1237 (P ¼ O), 1013
þ
(
P–O–C ); LC–MS (m/z, %): 470 (M þ H , 100); For
alip
C H N O PS ; calcd: 46.05; H, 4.29; N, 8.95%; found: C, (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
1
8
20
3
6
2
4
6.12; H, 4.21; N, 9.04%.
ethyl
1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
ꢁ
ylphosphoramidate (6f). Yield: 92%; solid, m.p. 238–240 C;
1
H NMR (DMSO-d ): 8.15 (s, 1H, ¼C–H), 7.53–7.25 (m,
(E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
6
5
H, Ar–H), 5.75 (s, 2H, –CH –), 4.50 (s, 1H,
2
ethyl benzo[d]thiazol-2-ylphosphoramidate (6c). Yield: 88%;
solid, m.p. 248–250 C; H NMR (DMSO-d ): 8.15 (s, 1H,
ꢁ
1
Pyrimidine–CH), 4.36 (m, 2H, O–CH CH ), 4.18 (q, 2H,
2
3
6
¼
C–H), 8.13 (d, J ¼ 8.0 Hz, 1H, Ar–H), 8.07 (d, J ¼ 7.6 Hz, P–O–CH
2
–), 3.64 (t, J ¼ 6.0 Hz, 2H, O–CH
2
–), 3.11 (s, 3H,
), 3.05 (s, 3H, N–CH ), 2.35 (s, 1H, N–H), 1.23 (t,
3 3
1
H, Ar–H), 7.53 (d, J ¼ 7.2 Hz, 2H, Ar–H), 7.49 (d, N–CH
13
J ¼ 7.6 Hz, 2H, Ar–H), 7.36 (t, J ¼ 7.2 Hz, 2H, Ar–H), 7.25 J ¼ 6.8 Hz, 3H, O–CH
CH ); C NMR (DMSO-d ): 171.2
2 3 6
(
–
t, J ¼ 6.4 Hz, 1H, Ar–H), 6.35 (s, 1H, N–H), 5.75 (s, 2H, (C-3), 163.2 (C-1), 161.4 (C-23), 160.4 (C-25), 150.2 (C-27),
CH –), 4.36 (m, 2H, O–CH CH ), 4.18 (q, 2H, 142.7 (C-6), 134.6 (C-7), 127.7 (C-9, C-11), 127.3 (C-8, C-
2 2 3
P–O–CH –), 3.64 (t, J ¼ 6.0 Hz, 2H, O–CH –), 1.23 (t, 12), 126.8 (C-10), 117.5 (C-5), 74.7 (C-24), 71.2 (C-13), 65.6
2
2
13
J ¼ 6.8 Hz, 3H, O–CH CH ); C NMR (DMSO-d ): 171.2 (C-15), 65.3 (C-16), 61.7 (C-20), 28.4 (C-29), 27.8 (C-30),
2
3
6
31
(
C-3), 163.2 (C-1), 151.4 (C-25), 142.7 (C-6), 134.6 (C-7), 16.4 (C-21); P NMR (DMSO-d ): 20.2 ppm; IR (KBr)
6
ꢀ
1
1
1
1
1
31.3 (C-30), 127.7 (C-9, C-11), 127.3 (C-8, C-12), 126.8 (C- (ꢀmax cm ): 3315 (NH), 1724, 1687 (C ¼ O), 1223 (P ¼ O),
þ
0), 124.9 (C-27), 124.6 (C-28), 120.9 (C-29), 117.8 (C-26), 1014 (P–O–Calip); LC–MS (m/z, %): 525 (M þ H , 100); For
17.5 (C-5), 73.7 (C-33), 71.2 (C-13), 65.6 (C-15), 65.3 (C- C H N O PS; calcd: C, 48.09; H, 4.80; N, 10.68%; found:
21
25
4
8
31
6), 61.7 (C-20), 16.4 (C-21);
P NMR (DMSO-d6): C, 48.16; H, 4.72; N, 10.77%.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
(E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
5.75 (s, 2H, –CH –), 4.36 (m, 2H, O–CH CH ), 4.18 (q, 2H,
2 2 3
ethyl 6-amino pyridin -2-ylphosphoramidate (6g). Yield: 90%; P–O–CH –), 3.64 (t, J ¼ 6.0 Hz, 2H, O–CH –), 2.39 (s, 3H,
2
2
ꢁ
1
solid, m.p. 291–293 C; H NMR (DMSO-d ): 8.16 (s, 1H, –CH ), 2.34 (s, 3H, –CH ), 1.23 (t, J ¼ 6.8 Hz, 3H,
6
3
3
13
¼
C–H), 7.53–7.25 (m, 5H, Ar–H), 7.09 (t, 1H, Py–H), 6.58 O–CH CH ); C NMR (DMSO-d ): 171.2 (C-3), 163.2 (C-
2 3 6
(
br–s, 2H, NH ), 5.84 (d, 2H, Py–H), 5.75 (s, 2H, –CH –), 1), 156.9 (C-26), 152.4 (C-23), 142.7 (C-6), 134.6 (C-7),
2
2
4
.36 (m, 2H, O–CH CH ), 4.18 (q, 2H, P–O–CH –), 3.64 (t, 127.7 (C-9, C-11), 127.3 (C-8, C-12), 126.8 (C-10), 117.5 (C-
2 3 2
J ¼ 6.0 Hz, 2H, O–CH –), 2.39 (s, 1H, NH), 1.23 (t, 5), 102.3 (C-27), 71.2 (C-13), 65.6 (C-15), 65.3 (C-16), 61.7
2
13
31
J ¼ 6.8 Hz, 3H, O–CH CH ); C NMR (DMSO-d ): 171.2 (C-20), 16.4 (C-21); 10.6 (C-29), 6.9 (C-28); P NMR
2
3
6
ꢀ
1
(
C-3), 163.2 (C-1), 159.4 (C-23), 154.6 (C-25), 142.7 (C-6), (DMSO-d
6
): 18.9 ppm; IR (KBr) (ꢀmax cm ): 3283 (NH),
1
1
7
2
3
38.6 (C-27), 134.6 (C-7), 127.7 (C-9, C-11), 127.3 (C-8, C- 1714, 1682 (C ¼ O), 1232 (P ¼ O), 1013 (P–O–Calip); LC–MS
þ
2), 126.8 (C-10), 117.5 (C-5), 100.5 (C-28), 96.1 (C-25), (m/z, %): 482 (M þ H , 100); For C20
H N O PS; calcd: C,
24 3 7
1.2 (C-13), 65.6 (C-15), 65.3 (C-16), 61.7 (C-20), 16.4 (C- 49.89; H, 5.02; N, 8.73%; found: C, 49.96; H, 5.10; N, 8.64%.
3
1
ꢀ1
1); P NMR (DMSO-d ): 19.3 ppm; IR (KBr) (ꢀ
cm ):
max
6
294 (NH), 1716, 1686 (C ¼ O), 1232 (P ¼ O), 1016
þ
In silico molecular docking studies with a-amylase
(
P–O–C ); LC–MS (m/z, %): 479 (M þ H , 100); For
alip
Molecular docking studies of the newly prepared com-
pounds were performed against a-amylase enzyme, in order
to understand the possible binding mechanism prior to their
synthesis. Marvin view software was utilized to optimize the
structures of the title compounds and the standard drug
acarbose. In order to reveal the binding modes of the title
compounds, docking simulation was performed targeting the
crystal structure of pancreatic alpha amylase which was
retrieved from RCSB, Protein Data Bank (PDB ID: 3IJ8) and
the structure was optimized by removing the water mole-
cules, hetero atoms and co-factors. Hydrogen bonds, missing
atoms and charges were computed. The PDB structures of
target protein (A) and standard drug, acarbose (B) are
shown in Figure S7 (see Supplemental materials). The
molecular docking method was performed using 1-click
docking online server tool (https://mcule.com), 1-click dock-
ing uses a Vina filter and dock multiple ligands into a single
target. Default binding site center specification of in 1-click
docking default binding site center X: 7.2178, Y: 16.2957, Z:
C H N O PS; calcd: C, 50.21; H, 4.85; N, 11.71%; found:
2
0
23
4
6
C, 50.07; H, 4.93; N, 11.79%.
(
E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
ethyl 1-methyl-1H-pyrazol-4-ylphosphoramidate (6h). Yield:
ꢁ
1
9
1
5%; solid, m.p. 256–259 C; H NMR (DMSO-d ): 8.16 (s,
6
H, ¼C–H), 7.76 (s, 1H, Pyrazole–H), 7.53–7.25 (m, 5H,
Ar–H), 7.21 (s, 1H, Pyrazole–H), 6.35 (s, 1H, N–H), 5.75 (s,
2
H, –CH –), 4.36 (m, 2H, O–CH CH ), 4.18 (q, 2H,
2 2 3
P–O–CH –), 3.86 (s, 3H, N–CH ), 3.64 (t, J ¼ 6.0 Hz, 2H,
2
3
13
O–CH –), 1.23 (t, J ¼ 6.8 Hz, 3H, O–CH CH ); C NMR
2
2
3
(
DMSO-d ): 171.2 (C-3), 163.2 (C-1), 142.7 (C-6), 134.6 (C-
6
7
), 131.2 (C-23), 129.2 (C-24), 127.7 (C-9, C-11), 127.3 (C-8,
C-12), 126.8 (C-10), 117.5 (C-5), 116.8 (C-27), 71.2 (C-13),
6
2
3
5.6 (C-15), 65.3 (C-16), 61.7 (C-20), 37.8 (C-28), 16.4 (C-
3
1
ꢀ1
1); P NMR (DMSO-d ): 22.1 ppm; IR (KBr) (ꢀ
cm ):
max
6
329 (NH), 1715, 1683 (C ¼ O), 1230 (P ¼ O), 1019
þ
(
P–O–C ); LC–MS (m/z, %): 467 (M þ H , 100); For
alip
C H N O PS; calcd: C, 48.92; H, 4.97; N, 12.01%; found:
1
9
23
4
6
4
2.1167. The docked process and interactions of compounds
C, 48.99; H, 4.89; N, 12.09%.
and protein were analyzed by using discovery studio visual-
[
40]
izer V16.1.0.15350.
(
E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
ethyl 5-methylpyrimidin-2-ylphosphoramidate (6i). Yield:
ꢁ
1
9
2
1%; solid, m.p. 277–279 C; H NMR (DMSO-d ): 8.48 (s, a-Amylase inhibitory activity
6
H, pyrimidine–H), 8.15 (s, 1H, ¼C–H), 7.53–7.25 (m, 5H, The a-amylase inhibitory activity had been executed employ-
[
36]
Ar–H), 6.35 (s, 1H, N–H), 5.75 (s, 2H, –CH –), 4.36 (m, ing standard procedure according to Nickavar and Amin
2
[
37]
2
H, O–CH CH ), 4.18 (q, 2H, P–O–CH –), 3.64 (t, which was at first proposed by Patil et al.
with minor
2
3
2
J ¼ 6.0 Hz, 2H, O–CH –), 2.29 (s, 3H, –CH ), 1.23 (t, changes (see Supplemental Materials for detailed procedure).
2
3
13
J ¼ 6.8 Hz, 3H, O–CH CH ); C NMR (DMSO-d ): 171.2
The IC50 values, concentration required to inhibit the
2
3
6
(
(
C-3), 165.5 (C-23), 163.2 (C-1), 156.8 (C-25, C-27), 142.7 a-amylase activity by 50% were calculated by a Fit Spline/
C-6), 134.6 (C-7), 127.7 (C-9, C-11), 127.3 (C-8, C-12), LOWESS analysis using a Graph Pad Prism 8.4.3 (686) soft-
1
26.8 (C-10), 117.5 (C-5), 116.4 (C-26), 71.2 (C-13), 65.6 ware for concentrations (X axis) versus percentage inhibition
(
C-15), 65.3 (C-16), 61.7 (C-20), 16.5 (C-29), 16.4 (C-21); (Y axis), and then row means with SD was calculated using
3
1
ꢀ1
P NMR (DMSO-d ): 20.7 ppm; IR (KBr) (ꢀmax cm ): grouped analysis.
6
3
315 (NH), 1718, 1687 (C ¼ O), 1228 (P ¼ O), 1015
þ
(P–O–C ); LC–MS (m/z, %): 479 (M þ H , 100); For
alip
Conclusion
C H N O PS; calcd: C, 50.21; H, 4.85; N, 11.71%; found:
2
0
23
4
6
C, 50.29; H, 4.78; N, 11.79%.
A series of PRs containing a heterocyclic moiety were syn-
thesized from 2,4-thiazolidinedione with high yields using
simple chemistry. Prior to their synthesis, molecular docking
(E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl
ethyl 4,5-dimethylisoxazol-3-ylphosphoramidate (6j). Yield: studies were performed to know their binding affinity
ꢁ
1
9
1
4%; solid, m.p. 247–248 C; H NMR (DMSO-d ): 8.16 (s, against pancreatic a-amylase enzyme. The compounds with
6
H, ¼C–H), 7.53–7.25 (m, 5H, Ar–H), 6.35 (s, 1H, N–H), good binding energy were provoked for synthesis. This is a

8
SK. MD. ALTAFF ET AL.
resource saving method which allowed us to synthesize
active compounds without waste of time and chemicals.
Further, all the synthesized compounds were screened
in vitro for their ability to inhibit a-amylase using spectro-
photometric method. The compounds exhibited good to
moderated inhibition toward the target enzyme when com-
pared with the standard drug, acarbose. Especially com-
pound 6f, 6c, 6d and 6j exhibited good inhibition with IC50
values in the range 54.14 ± 0.35 to 65.65 ± 0.22 mg/mL in
comparison with standard (50.47 ± 0.28 mg/mL). The present
investigation demonstrate that the synthesized compounds
will be the promising next generation anti-diabetic drugs,
which can be effectively used in the treatment of symptom
of diabetic complications.
[4] Kaur, R.; Dahiya, L.; Kumar, M. Fructose-1,6-Bisphosphatase
Inhibitors: A New Valid Approach for Management of Type 2
Diabetes Mellitus. Eur. J. Med. Chem. 2017, 141, 473–505. DOI:
10.1016/j.ejmech.2017.09.029.
[
5] (a) Dirven, H. A. A. M.; Van Ommen, B.; Van Bladeren, P.
Glutathione Conjugation of Alkylating Cytostatic Drugs with a
Nitrogen Mustard Group and the Role of Glutathione S-
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1021/tx950143c. (b) Niculescu-Duvaz, I.; Spooner, R.; Marais,
R.; Springer, C. J. Gene-Directed Enzyme Prodrug Therapy.
Bioconjug. Chem. 1998, 9, 4–22. DOI: 10.1021/bc970116t.
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[
6] Patocka, J. Acetylcholinesterase Inhibitors – From Nervous Gas
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Mason, M. D. Naphthyl Phosphoramidate Derivatives of BVdU
as Potential Anticancer Agents: Design, Synthesis and Biological
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Acknowledgments
Cahard, D.; Sheeka, H. M.; De Clercq, E.; Balzarini, J. Aryl
Phosphoramidate Derivatives of d4T Have Improved anti-HIV
Efficacy in Tissue Culture and May Act by the Generation of a
Novel Intracellular Metabolite. J. Med. Chem. 1996, 39,
The authors thank Prof. W. Rajendra, Division of Molecular Biology,
Department of Zoology, S. V. University, Tirupati, for his support in
biological activity studies. The authors also acknowledge to Dr. C.
Naga Raju, Department of Chemistry, S. V. University, Tirupati, for his
constant support to complete this work.
1748–1753. DOI: 10.1021/jm950605j. (c) McGuigan, C.; Harris,
S. A.; Daluge, S. M.; Gudmundsson, K. S.; McLean, E. W.;
Burnette, T. C.; Marr, H.; Hazen, R.; Condreay, L. D.; Johnson,
L.; et al. Application of Phosphoramidate Pronucleotide
Technology to Abacavir Leads to a Significant Enhancement of
Antiviral Potency. J. Med. Chem. 2005, 48, 3504–3515. DOI: 10.
1021/jm0491400. (d) Perrone, P.; Luoni, G. M.; Kelleher, M. R.;
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Disclosure statement
The authors declare no conflict of interest.
0
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